`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`ALLERGAN, INC.,
`Patent Owner.
`
`_____________________________
`
`Patent No. 8,648,048
`
`_____________________________
`
`
`
`DECLARATION OF MANSOOR AMIJI, PH.D.
`
`
`
`TEVA - EXHIBIT 1002
`
`
`
`TABLE OF CONTENTS
`
`
`I.
`
`QUALIFICATIONS ........................................................................................... 1
`
`II.
`
`SCOPE OF WORK ............................................................................................ 3
`
`III. OVERVIEW OF THE ’048 PATENT .................................................................... 3
`
`IV. FILE HISTORY OF THE ’048 PATENT ................................................................ 7
`
`V.
`
`LEGAL STANDARDS ..................................................................................... 11
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME ........................................ 14
`
`VII. CLAIM CONSTRUCTION ................................................................................ 15
`
`VIII. THE STATE OF THE ART................................................................................ 20
`
`IX. ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE CLAIMED
`FEATURES OF THE ’048 PATENT ................................................................... 28
`
`
`
`
`
`
`
`GROUND 1. THE TEACHINGS OF DING ’979 AND SALL MAKE CLAIMS
`1-10, 12-14, 16-20, 22, AND 23 OBVIOUS. .................................................... 43
`
`GROUND 2. THE TEACHINGS OF DING ’979, SALL, AND ACHEAMPONG
`MAKE CLAIMS 11 AND 21 OBVIOUS. ............................................................ 59
`
`GROUND 3. THE TEACHINGS OF DING ’979, SALL, AND GLONEK
`MAKE CLAIM 15 OBVIOUS. .......................................................................... 62
`
`X. NO UNEXPECTED RESULTS ........................................................................... 64
`
`XI. CONCLUDING STATEMENTS .......................................................................... 79
`
`XII. APPENDIX – LIST OF EXHIBITS ..................................................................... 80
`
`
`
`i
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`
`
`I, Mansoor Amiji, declare as follows:
`
`I.
`
`QUALIFICATIONS
`
`1. My name is Mansoor Amiji. I am currently the Bouvé College
`
`Distinguished Professor in the Department of Pharmaceutical Sciences in the
`
`School of Pharmacy at Northeastern University. I have been a member of the
`
`faculty at Northeastern since 1993. I am also an affiliate faculty member in the
`
`Departments of Chemical Engineering and Biomedical Engineering within the
`
`College of Engineering at Northeastern, as well as a Distinguished Adjunct
`
`Professor within the Faculty of Pharmacy at King Abdulaziz University.
`
`2.
`
`I received a B.S. in Pharmacy from Northeastern University in 1988,
`
`and a Ph.D. in Pharmaceutics/Biomaterials Science from Purdue University in
`
`1992. I have also conducted research as a Senior Research Scientist at the
`
`Columbia Research Laboratories in Madison, Wisconsin, as well as served as a
`
`Visiting Research Scholar in the Department of Chemical Engineering at MIT.
`
`3. My current research focuses on the development of biocompatible
`
`materials from natural and synthetic polymers, target-specific drug and gene
`
`delivery systems for cancer and infectious diseases, and nanotechnology
`
`applications for medical diagnosis, imaging and therapy. I have extensive
`
`experience with pharmaceutical formulations, including oil-in-water emulsions
`
`containing various types of oils, including castor oil, as well as with sterile
`
`formulations and dosage forms for use in the eye. I have also taught courses on the
`
`development and characterization of ophthalmic formulations to undergraduate
`
`pharmacy and graduate students.
`
`1
`
`
`
`4.
`
`I have had extensive experience in the development and
`
`characterization of lipid-based drug delivery systems, including oil-in-water
`
`emulsion formulations intended for parenteral and oral administration. I have also
`
`worked on emulsion formulations that are targeted to different parts of the body,
`
`including the brain.
`
`5. My research has been funded by such organizations as the National
`
`Institute of Health (NIH) and the National Science Foundation (NSF), as well as
`
`other government agencies and foundations. I also serve, or have served, on the
`
`editorial board of thirteen peer-reviewed journals such as Drug Design:
`
`Development and Therapy, Expert Opinion on Drug Delivery, Pharmaceutical
`
`Formulations and Quality, and Tissue Barriers. I have also served as a reviewer
`
`for 39 peer-reviewed journals including Science, Angewandte Chemie
`
`International Edition, European Journal of Pharmaceutical Sciences, Journal of
`
`Pharmaceutical Sciences, and Nature Communications.
`
`6.
`
`I have authored or co-authored more than 200 peer-reviewed journal
`
`articles. I have also authored 43 book chapters and been listed as an inventor on 16
`
`patents and patent applications. I have given over 170 invited seminars at
`
`scientific symposia and educational institutions.
`
`7.
`
`I have received numerous honors and awards, including my 2014
`
`induction into the College of Fellows at the Controlled Release Society,
`
`appointment as an Honorary Member in the Phi Lambda Sigma Pharmacy
`
`Leadership Society, a fellowship as well as the Meritorious Manuscript Award
`
`2
`
`
`
`from the American Association of Pharmaceutical Sciences, and the Eurand Award
`
`for Outstanding Research in Oral Drug Delivery.
`
`8.
`
`A summary of my education, experience, publications, awards and
`
`honors, patents, publications, and presentations is provided in my CV, a copy of
`
`which is submitted separately. Ex. 1003.
`
`II.
`
`SCOPE OF WORK
`
`9.
`
`I understand that a petition is being filed with the United States Patent
`
`and Trademark Office for Inter Partes Review of U.S. Patent No. 8,648,048 (“the
`
`’048 patent,” Ex. 1001). I have been retained by the Petitioner as a technical
`
`expert to provide analysis and opinions regarding the ’048 patent. I have reviewed
`
`the ’048 patent and relevant sections of its prosecution history in the United States
`
`Patent and Trademark Office. Ex. 1004. I have also reviewed and considered
`
`various other documents in arriving at my opinions, and cite them in this
`
`declaration. For convenience, documents cited in this declaration are listed in the
`
`Appendix in Section XII.
`
`10.
`
`I am compensated at the rate of $870/hour for my work. I have no
`
`financial interest in the outcome of this matter.
`
`III. OVERVIEW OF THE ’048 PATENT
`
`11. The ’048 patent issued February 11, 2014. The ’048 patent is entitled
`
`“Methods of Providing Therapeutic Effects using Cyclosporin Components.” The
`
`first page of the patent states that an application for the ’048 patent (U.S.
`
`Application No. 13/967,168, “the ’168 application”) was filed on August 14, 2013
`
`and claims priority through a series of continuations to U.S. Application No.
`
`3
`
`
`
`10/927,857 (“the ’857 application,” Ex. 1005), and thereby to U.S. Provisional
`
`Patent Application No. 60/503,137, filed on September 15, 2003.
`
`12. The ’048 patent is generally directed to methods of treatment of
`
`ocular disorders using pharmaceutical compositions of cyclosporin A (referred to
`
`herein as “CsA”). Claim 1 of the ’048 patent recites the following:
`
`
`A method of increasing tear production in the eye of a human, the
`
`1.
`
`method comprising topically administering to the eye of the human in need
`
`thereof an emulsion at a frequency of twice a day, wherein the emulsion
`
`comprises cyclosporin A in an amount of about 0.05% by weight,
`
`polysorbate 80, acrylate/C10-30 alkyl acrylate cross-polymer, water, and
`
`castor oil in an amount of about 1.25% by weight; and
`
`wherein the topical ophthalmic emulsion is effective in
`
`increasing tear production.
`
`Ex. 1001, col. 15, ll. 15-23.
`
`13. Claim 2 depends from claim 1 and recites that the emulsion further
`
`comprises a tonicity agent or a demulcent component. Claim 3 further depends
`
`from claim 2, and recites that the tonicity agent or demulcent component is
`
`glycerine. Claim 4 depends from claim 1, reciting that the emulsion further
`
`comprises a buffer; claim 5 further depends from claim 4, and recites that the
`
`buffer is sodium hydroxide. Claims 6-9 also depend from claim 1, reciting that the
`
`topical ophthalmic emulsion further comprises glycerine and a buffer, that the
`
`emulsion comprises polysorbate 80 in an amount of 1.0% by weight, that the
`
`emulsion comprises acrylate/C10-30 alkyl acrylate cross-polymer in an amount of
`
`about 0.05% by weight, and that the emulsion further comprises glycerine in an
`
`amount of 2.2% by weight and a buffer, respectively. Claim 10 depends from
`
`4
`
`
`
`claim 9, reciting that the buffer is sodium hydroxide. Percent values refer to % by
`
`weight throughout this declaration unless otherwise indicated.
`
`14. Claim 11 depends from claim 1, reciting, “when the emulsion is
`
`administered to an eye of a human in an effective amount in increasing tear
`
`production, the blood of the human has substantially no detectable concentration of
`
`cyclosporin A.” Id. at col. 15, ll. 44-47. Claim 12 depends from claim 6, reciting
`
`that the emulsion has a pH in the range of about 7.2 to about 7.6. Claims 13 and 14
`
`depend from claim 1, reciting respectively that the emulsion is “as substantially
`
`therapeutically effective as” and “achieves at least as much therapeutic
`
`effectiveness as,” a similar emulsion comprising CsA in an amount of 0.10% by
`
`weight and castor oil in an amount of 1.25% by weight. Id. at col. 15, l. 50 – col.
`
`16, l. 3. Similarly, claim 15 depends from claim 1, reciting that the emulsion
`
`breaks down more quickly in the eye of a human, “thereby reducing vision
`
`distortion” as compared to a second emulsion that contains only 50% as much
`
`castor oil. Id. at col. 16, ll. 4-8. Claim 16 depends from claim 1, reciting that the
`
`emulsion, when administered to the human eye, demonstrates “a reduction in
`
`adverse events” as compared to a second emulsion comprising 0.10% by weight
`
`CsA and 1.25% castor oil. Id. at col. 16, ll. 9-14. Claim 17 further depends from
`
`claim 16, reciting that the adverse events are side effects.
`
`15. Claim 18 of the ’048 patent is an independent claim to a method of
`
`treatment, and recites the following:
`
`18. A method of treating keratoconjunctivitis sicca, the
`
`method comprising the step of topically administering to an eye of a
`
`5
`
`
`
`human in need thereof an emulsion at a frequency of twice a day, the
`
`emulsion comprising:
`
`cyclosporin A in an amount of about 0.05% by weight;
`
`castor oil in an amount of 1.25% by weight;
`
`polysorbate 80 in an amount of about 1.0% by weight;
`
`acrylate/C10-30 alkyl acrylate cross-polymer in an amount of about
`
`0.05% by weight;
`
`a tonicity component or a demulcent component in an amount of
`
`about 2.2% by weight;
`
`a buffer; and
`
`water;
`
`wherein the emulsion is effective in treating
`
`keratoconjunctivitis sicca and wherein the topical ophthalmic
`
`emulsion has a pH in the range of about 7.2 to about 7.6.
`
`Id. at col. 16, ll. 17-32.
`
`16. Claims 19-21 depend from claim 18, and recite that the buffer is
`
`sodium hydroxide, the tonicity/demulcent component is glycerine, and that “when
`
`the emulsion is administered to the eye of a human in an effective amount in
`
`treating keratoconjunctivitis sicca, the blood of the human has substantially no
`
`detectable concentration of the cyclosporin A.” Id. at col. 16, ll. 37-41.
`
`17. Claim 22 of the ’048 patent is an independent claim to a method for
`
`the treatment of keratoconjunctivitis sicca, and recites the following:
`
`22. A method comprising:
`
`administering an emulsion topically to the eye of a human having
`
`keratoconjunctivitis sicca at a frequency of twice a day, wherein the
`
`emulsion comprises:
`
`cyclosporin A in an amount of about 0.05% by weight;
`
`castor oil in an amount of about 1.25% by weight;
`
`6
`
`
`
`polysorbate 80 in an amount of about 1.0% by weight;
`
`acrylate/C10-30 alkyl acrylate cross-polymer in an amount of about
`
`0.05% by weight;
`
`glycerine in an amount of about 2.2% by weight;
`
`sodium hydroxide; and
`
`water; and
`
`wherein the emulsion is effective in increasing tear production in the
`
`human having keratoconjunctivitis sicca.
`
`Id. at col. 16, ll. 42-55. Finally, claim 23 depends from claim 22, reciting
`
`that the emulsion has a pH in the range of about 7.2 to about 7.6.
`IV. FILE HISTORY OF THE ’048 PATENT
`
`18. As noted above, the instant patent that issued from the ’168
`
`application resulted from continuations of the ’857 application. During
`
`prosecution of the ’857 application, the applicant expressly admitted that the
`
`emulsion, referred to as Composition II, and which remains the emulsion recited
`
`in the method of treatment claims in the ’048 patent, was squarely within the
`
`teachings of U.S. Patent No. 5,474,979 (filed May 17, 1994) to Ding et al. (“Ding
`
`’979,” Ex. 1006). The applicant stated:
`
`The applicants concede that it would have been obvious to modify
`
`examples 1A-1E of the Ding [’979] reference to arrive at Composition
`
`II of the present application. The differences are insignificant. One
`
`need only use the cyclosporin concentration of Example 1E (0.05%),
`
`the castor oil concentration of Example 1D (1.250%), and the
`
`remaining ingredients of those examples. As the examiner correctly
`
`observes, one of ordinary skill in the art “would readily envisage”
`
`such a composition, especially in view of Example 1B: having
`
`selected 0.05% as the concentration of cyclosporin, Example 1B
`
`7
`
`
`
`(wherein the ratio of cyclosporin to castor oil is 0.04) teaches that the
`
`concentration of castor oil should be 1.250% (0.05% / 1.250% =
`
`0.04). The applicants concede that in making this selection (0.05%
`
`cyclosporin and 1.250% castor oil) there would have been a
`
`reasonable expectation of success; the differences between Examples
`
`1A-1E and Composition II are too small to believe otherwise.
`
`The formulation of Composition II is squarely within the teachings of
`
`the Ding [’979] reference, and the Office should disregard any
`
`statements by the applicants suggesting otherwise[.]
`
`Ex. 1005 at 0435.
`
`As discussed below, I agree with these statements.
`
`19.
`
`I have reviewed the content of the ’857 application concurrently with
`
`that of the ’048 patent and find Composition II of the ’857 application to be
`
`indistinguishable from the emulsion claimed in the ’048 patent. A table submitted
`
`by the applicant during prosecution of the ’857 application has been included
`
`below, and extended to include the emulsion of the ’048 patent for convenient
`
`comparison.
`
`8
`
`
`
`
`
`Ex. 1005 at 0434 (right-most column added). The ’857 application was ultimately
`
`abandoned. Ex. 1004 at 0002.
`
`20. As mentioned above, the ’168 application resulted from a series of
`
`continuations from the abandoned ’857 application. Id. During prosecution of the
`
`’168 application, the applicants acknowledged their prior admissions, stating that
`
`they had been collecting evidence to support the patentability of the claims “[s]ince
`
`these comments have been filed.” Ex. 1004 at 0007. The examiner thereafter
`
`rejected the claims under 35 U.S.C. § 103 as being obvious over Ding ’979 and for
`
`double patenting over Ding ’979. Id. at 0178-92.
`
`21. On October 3, 2013, the examiner conducted an interview with four
`
`representatives of applicants. Id. at 0246. According to the applicants’ interview
`
`summary, the applicants presented “Data demonstrating unexpected results and
`
`commercial success of the claimed method” and “Data and information regarding
`
`the claimed method’s satisfaction of a long-felt need.” Id. Applicants’ principal
`
`9
`
`
`
`argument was that “the evidence of non-obviousness presented at the interview
`
`overcomes the prima facie obviousness rejection.” Id.
`
`22. On October 14, 2013, the applicants amended the claims to, among
`
`other things, substitute the generic term “acrylate/C10-30 alkyl acrylate cross-
`
`polymer” for the trade name Pemulen® and substitute the full term
`
`“keratoconjunctivitis sicca” for the acronym “KCS.” Id. at 0240-45. The applicants
`
`stated without elaboration that “the prima facie case of obviousness has not been
`
`properly established against the pending claims,” but based their argument on their
`
`assertion that “the unexpected results, commercial success, and satisfaction of long
`
`felt need obtained with the claimed methods and the failure of others overcome the
`
`prima facie obviousness rejection asserted in the Office Action.” Id. at 0247. The
`
`applicants submitted four declarations in support of their assertions: two by Rhett
`
`Schiffman, one by Mayassa Attar, and one by Aziz Mottiwala. Specifically,
`
`applicants argued, based on one Schiffman declaration (“Schiffman Declaration
`
`1”) and the Attar Declaration that “there are new and unexpected results
`
`relative to the prior art.” Id. at 0248 (emphasis in original). The applicants
`
`relied on “unexpected results compared to the prior art” in Schirmer Tear Testing
`
`and decreased corneal staining, as well as reduction of blurred vision and
`
`decreased use of artificial tears. Id. I discuss Schiffman Declaration 1, as well as
`
`the Attar declaration, in Section X below.
`
`23. The examiner issued a Notice of Allowance on December 2, 2013. Id.
`
`at 0461. The examiner concluded that applicants had failed to demonstrate
`
`commercial success or long-felt need. Id. at 0469-71. However, relying on
`
`10
`
`
`
`Schiffman Declaration 1 and the Attar Declaration, the examiner concluded that,
`
`“the specific combination of 0.05% by weight cyclosporin A with 1.25% by weight
`
`castor oil is surprisingly critical for therapeutic effectiveness in the treatment of
`
`dry eye or keratoconjunctivitis sicca,” and therefore, “demonstrate[s] surprising
`
`and unexpected results.” Id. at 0473.
`
`24. As set forth in detail throughout this declaration, I disagree with the
`
`opinions of Dr. Schiffman and Dr. Attar that the results in the submitted
`
`declarations were unexpected or surprising.
`
`V. LEGAL STANDARDS
`
`25.
`
`I understand that a claim is not patentable under 35 U.S.C. § 102, for
`
`lack of novelty, if each and every element of the claim is described, either
`
`expressly or inherently, in a single prior art reference.
`
`26.
`
`I have been informed that a claimed invention is not patentable under
`
`35 U.S.C. § 103, for obviousness, if the differences between the invention and the
`
`prior art are such that the subject matter as a whole would have been obvious at the
`
`time the invention was made to “a person having ordinary skill in the art” to which
`
`the subject matter of the invention pertains. I understand that “a person of ordinary
`
`skill in the art” is a hypothetical person who is presumed to have known the
`
`relevant art at the time of the invention. As discussed above, I understand that prior
`
`art for the purpose of this declaration includes references that were published at
`
`least before September 15, 2003.
`
`27.
`
`I have been instructed that, a determination of obviousness requires
`
`inquiries into (i) the scope and content of the art when the invention was made; (ii)
`
`11
`
`
`
`the differences between the art and the claims at issue; (iii) the level of ordinary
`
`skill in the pertinent art when the invention was made; and, to the extent they exist,
`
`any secondary considerations.
`
`28.
`
`I understand that a claim can be found to be obvious if all the claimed
`
`elements were known in the prior art and one skilled in the art could have
`
`combined the elements as claimed by known methods with no change in their
`
`respective functions, and the combination would have yielded nothing more than
`
`predictable and expected results to one of ordinary skill in the art.
`
`29.
`
`I understand that improper hindsight must not be used when
`
`comparing the prior art to the invention for obviousness. Thus, a conclusion of
`
`obviousness must be firmly based on the knowledge and skill of a person of
`
`ordinary skill in the art at the time the invention was made.
`
`30.
`
`I have been informed that obviousness may also be shown by
`
`demonstrating that it would have been obvious to modify what is taught in a single
`
`piece of prior art to create the patented invention. I understand that obviousness
`
`may be demonstrated by showing that it would have been obvious to combine the
`
`teachings of more than one item of prior art. I understand that in order for a
`
`combination of references or teachings to render the claimed invention obvious,
`
`there must be some supporting rationale for combining the cited references or
`
`teachings as proposed.
`
`31.
`
`I am informed that the following are examples of principles that may
`
`indicate that it would have been obvious to combine multiple teachings, resulting
`
`in the claimed combination, if the claimed combination involves: (i) the
`
`12
`
`
`
`combination of prior art elements according to known methods to yield predictable
`
`results; (ii) the simple substitution of one known element for another to obtain
`
`predictable results; (iii) the use of a known technique to improve similar methods
`
`or products in the same way; (iv) the application of a known technique to a known
`
`method or product ready for improvement to yield predictable results; (v) the
`
`application of a technique or approach that would have been “obvious to try” (e.g.,
`
`choosing from a finite number of identified, predictable solutions, with a
`
`reasonable expectation of success); (vi) predictable variations of a known work in
`
`one field of endeavor prompted for use in either the same field or a different field
`
`based on design incentives or other market forces; or (vii) some teaching,
`
`suggestion, or motivation in the prior art that would have led one of ordinary skill
`
`to modify the prior art reference or to combine prior art reference teachings to
`
`arrive at the claimed invention.
`
`32.
`
`I also understand that “secondary considerations” may be weighed
`
`against evidence of obviousness where appropriate.
`
`33.
`
`I understand that such secondary considerations, where in evidence,
`
`may include: (i) commercial success of a product due to the merits of the claimed
`
`invention; (ii) a long-felt, but unsatisfied need for the invention; (iii) failure of
`
`others to find the solution provided by the claimed invention; (iv) deliberate
`
`copying of the invention by others; (v) unexpected results achieved by the
`
`invention; (vi) praise of the invention by others skilled in the art; (vii) lack of
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`independent simultaneous invention within a comparatively short space of time;
`
`and (viii) teaching away from the invention in the prior art. Secondary
`
`13
`
`
`
`considerations are relevant where there is a nexus between the evidence and the
`
`claimed invention.
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME
`
`34.
`
`I have been advised that “a person of ordinary skill in the relevant
`
`field” is a hypothetical person who is presumed to have known the relevant art at
`
`the time of the invention. A person of ordinary skill in the art is also a person of
`
`ordinary creativity. I understand that the relevant timeframe for assessing the
`
`validity of claims of the ’048 patent for the purposes of this declaration is assumed
`
`to be September 15, 2003, the earliest alleged priority date of the application that
`
`led to the ’048 patent. Unless otherwise specifically noted, all of my opinions
`
`expressed herein regarding a person of ordinary skill in the art apply to a person of
`
`ordinary skill in the art as of September 15, 2003.
`
`35. By virtue of my education, experience, and training, I am familiar
`
`with the level of skill in the art of the ’048 patent prior to September 15, 2003. In
`
`my opinion, a person of ordinary skill in the relevant field as of September 15,
`
`2003 would typically have an advanced degree, such as a medical degree, or a
`
`Ph.D. in organic chemistry, pharmaceutical chemistry, medicinal chemistry,
`
`pharmaceutics, physical pharmacy, or a related field, or could have less education
`
`but considerable professional experience in one or more of these fields.
`
`Additionally, a person of ordinary skill in the art would have been aware of the
`
`information known in the art relating to dry eye/KCS, its causes and known, useful
`
`treatments, whether palliative or therapeutic.
`
`14
`
`
`
`36.
`
`In particular, one of ordinary skill in the art would likely have some
`
`combination of the following skills and experience: (i) experience formulating
`
`pharmaceutical products; (ii) experience designing and preparing drug
`
`formulations intended for topical ocular administration; (iii) the ability to
`
`understand results and findings presented or published by others in the field,
`
`including the publications discussed in this declaration.
`
`VII. CLAIM CONSTRUCTION
`
`37.
`
`I have been advised that, in the present proceeding, the ’048 patent
`
`claims are to be given their broadest reasonable interpretation in view of the
`
`specification. I also understand that, absent some reason to the contrary, claim
`
`terms are typically given their ordinary and accustomed meaning as would be
`
`understood by one of ordinary skill in the art. I have followed these principles in
`
`my analysis throughout this declaration. The ’048 patent provides definitions for
`
`certain claim terms. In my opinion, these definitions are conventional. Certain
`
`claim terms are not defined in the ’048 patent. I discuss a few terms below and
`
`what I understand as constructions of these terms.
`
`38. Claims 4-6, 9, 10, 18, and 19 recite that the emulsion of the claimed
`
`method comprises a “buffer,” while claims 5, 10, and 19 recite that “the buffer is
`
`sodium hydroxide.” As discussed in the specification, “[t]he pH of the emulsions
`
`can be adjusted in a conventional manner using sodium hydroxide . . . to a
`
`physiological pH level.” Ex. 1001, col. 12, ll. 15-17. The specification also notes
`
`that “suitable buffer components, for example, and without limitation, phosphates,
`
`citrates, acetates, borates and the like and mixtures thereof, may be employed to
`
`15
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`
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`maintain a suitable pH.” Id. at col. 12, ll. 22-25. Based on the specification of the
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`’048 patent, a person of ordinary skill in the art would understand the term “buffer”
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`to include “sodium hydroxide.”
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`39. Claims 11 and 21 recite that following administration of the claimed
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`emulsion, “the blood of a human has substantially no detectable concentration of
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`the cyclosporin A.” According to the specification: “Cyclosporin component
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`concentration in blood preferably is determined using a liquid chromatography-
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`mass spectroscopy-mass spectroscopy (LC-MS/MS), which test has a cyclosporin
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`component detection limit of 0.1 ng/ml. Cyclosporin component concentrations
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`below or less than 0.1 ng/ml are therefore considered substantially undetectable.”
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`Ex. 1001, col. 5, l. 64 – col. 6, l. 3. Notably, neither the claims nor the specification
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`discuss the time point at which the blood levels of CsA are measured. A person of
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`ordinary skill in the art could measure blood concentration at either peak or trough
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`levels, e.g., taking blood samples at serial time points, and determining the
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`maximal concentration, or by taking and testing a blood sample just prior to a
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`second administration of the drug to determine the trough level of the drug in the
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`blood. Taking the broadest reasonable construction for the purposes of this
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`proceeding, the phrase “substantially no detectable concentration” of CsA includes
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`CsA blood levels measured at a concentration below 0.1 ng/mL taken at either
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`peak or trough levels.
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`40.
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`Independent claim 1 states that the emulsion is “effective in increasing
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`tear production” and independent claim 22 states that the emulsion is “effective in
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`increasing tear production in the human having keratoconjunctivitis sicca
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`16
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`
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`[(KCS)].” Independent claim 18 states that the emulsion is “effective in treating
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`keratoconjunctivitis sicca [(KCS)].” The ’048 patent characterizes KCS as “an
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`absolute or partial deficiency in aqueous tear production.” Ex. 1001, col. 3, ll. 2-5;
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`see also STEDMAN’S MEDICAL DICTIONARY 27TH
` EDITION (M.B. Pugh ed. 2000)
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`(“Stedman’s,” Ex. 1022) at 0003 (KCS is an “inflammation of the conjunctive and
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`of the cornea” that is “associated with decreased tears” and is a synonym of dry
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`eye syndrome). During prosecution, the applicants relied on an increase in tearing
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`as demonstrated by the Schirmer Tear Test to assert unexpected efficacy of the
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`claimed emulsion for treating dry eye disease/KCS. See, e.g., Ex. 1004 at 0253
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`(arguing that the claimed method was “therapeutically effective for the treatment
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`of dry eye or [KCS] . . . according to corneal staining score, Schirmer score,” and
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`other measures). In light of the discussion above and in the context of the
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`specification of the ’048 patent, I understand that an emulsion effective in
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`increasing tear production is an example of an emulsion effective in treating KCS.
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`41. Dependent claims 13 and 14 respectively describe the emulsion as
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`being “as substantially therapeutically effective as” and having “at least as much
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`therapeutic effectiveness as” a second emulsion with 0.10% CsA and 1.25% castor
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`oil. The word “therapeutic” means “[r]elating to . . . the treatment, remediating, or
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`curing of a disorder or disease.” Ex. 1022 at 0007. This includes palliative
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`treatments, which focus on remediation of a disease—i.e., they alleviate the
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`symptoms of the disease. Id. at 0004-05. This comports with what the art
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`recognized as a treatment for dry eye disease/KCS. See Medications for Dry Eye
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`(1999) In PHYSICIANS’ DESK REFERENCE FOR OPHTHALMOLOGY (27th ed.)
`
`17
`
`
`
`Montvale, NJ: PDR Network (“Ophthalmic PDR,” Ex. 1013) at 13 (“Dry eye is
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`treated with artificial tear preparations and ophthalmic lubricants.”) A person of
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`ordinary skill in the art would not understand the phrases “therapeutically
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`effective” or “therapeutic effectiveness” to be limited to treatment of an immune-
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`mediated response sometimes contributing to the condition.
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`42. Claims 13 and 14 each depend from claim 1, and therefore a person of
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`ordinary skill in the art would understand the phrases “as substantially
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`therapeutically effective as” and “at least as much therapeutic effectiveness as” to
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`refer back to the efficacy recited in claim 1, “effective in increasing tear
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`production.” Even if these phrases were understood somehow to import the term
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`“keratoconjunctivitis sicca” found in independent claim 18, but not in claims 1 or
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`13-14, a person of ordinary skill would still understand the phrases to include
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`efficacy in increasing tear production because, as discussed above, an emulsion
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`effective in increasing tear production is an example of an emulsion effective in
`
`treating KCS. Accordingly, the plain meanings of these terms include “as
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`substantially therapeutically effective in increasing tear production as” and “at
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`least as much therapeutic effectiveness in increasing tear production as.”
`
`43. Claims 16 and 17 respectively recite that the emulsion of the claimed
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`method has fewer “adverse events” relative to a second emulsion, and that the
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`“adverse events” are “side effects.” The specification further refers to adverse
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`events as “e.g. side effects, drug interactions and the like.” Ex. 1001, col. 15, ll. 1-
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`8. The plain meaning of the phrase “side effects” is “A result of a drug or other
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`therapy in addition to or in extension of the desired therapeutic effect; usually but
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`18
`
`
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`not necessarily, denoting an undesired effect.” Ex. 1022 at 0006. Accordingly, I
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`understand “adverse events” to include undesirable side effects as well as other
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`negative reactions to the drug. In the context of an agent topically administered to
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`the eye, undesirable side effects commonly include burning, stinging, and general
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`eye pain. See Ex. 1007 at 636, Table 3.
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`44. The specification also gives an example of side effects “which may
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`result from the presence of the cyclosporin component in the blood of the human
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`or animal being treated.” Id. at col. 4, ll. 63 – col. 5, ll. 1. The ’048 patent also
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`teaches “[o]ne of the important advantages of the present invention is the reduced
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`concentration of the cyclosporin component in the blood of